CurrentestimatesfortheannualtreatmentofUTIsintheUSincludingrecurrencesandtheir complicationsexceed$3.5billion.AsignificantnumberofUTIsarerecurrent(recUTIs),withthe samesubjectexperiencingmultipleboutsofinfection.AfrequentoutcomeofrecUTIsislossin bladdercontrolwhichismanifestedasincreasedurgencyandfrequencyaccompaniedbyloss ofbladdercapacity.Inspiteoftheseverediscomfortandanxietyassociatedwiththiscondition, theunderlyingbasisforbladderimpairmenthasremainedunresolved.Inanexperimental mousemodelofUPEC-inducedrecUTIs,weobservedexuberantsproutingofsensoryand sympatheticnerveswasobservedinthemousebladder,whichcloselyparalleledincreased bladderfrequencyandreducedbladdercapacityintheinfectedmice.Theseobservations suggestthatbladdernervefibersactivelyrespondtobacterialinfectionsandtheseresponses couldpotentiallycontributetolossofbladderdysfunction.Sinceaknowndeterminantofnerve cellssproutinginthebladderisnervegrowthfactor(NGF)welookedforpossiblesourcesofthis growthfactor.Wehaveidentifiedmastcells(MCs)andmonocytesasputativecellularsources ofNGFasmicesubjectedtorecUTIscontainlargenumberofrecruitedmonocytescomparedto navemiceandMCdeficientmicedonotanylossofbladdercontrolevenafterrecUTIs. Therefore,wehypothesizethatthelossofbladdercontrolafterrecUTIs,isthedirectresultof nervefiberhyperplasiawhichisinducedbyNGFandotherneurotrophicfactorsproducedby localMCsandMCrecruitedmonocytes.Wefurtherhypothesizethatitispossibletoprevent lossofbladdercontrolinmicesubjectedtorecUTIsbytherapeutictargetingofNGFandother neurotrophicfactors.Tovalidatethesenotions,wehaveproposedthefollowingspecificaims:(i) Establishaclearlinkbetweenneuronalsproutingandlossofbladdercontrolinmicesubjected torecUTIs;?(iii)ExaminetheroleofneurotrophicfactorsinbladderdysfunctionfollowingrecUTIs andtheeffectoftargetingthesefactorstoprotectandevenreversebladderdysfunction(iii) InvestigatethecontributionofMCstoneuronalsproutingandbladderimpairment.